Congenital brain damage due to intrauterine virus infections is a significant pediatric problem. In addition, the brain continues to develop during the first year of postnatal life. Since the developing nervous system is uniquely sensitive to damage following virus infection, administering neurovirulent vaccines to infants can place the child's nervous system at increased risk for vaccine related injury. Mumps virus, and certain strains of mumps vaccine (Urabe Am9, Leningrad 3), are among the most neurotropic of the early childhood viruses, and new MMR combinations continue to be proposed, including new strains of mumps vaccine virus. In addition, vaccine neurovirulence concerns have been raised about other viruses including influenza virus, human parainfluenza virus III, poliovirus, dengue virus, Japanese encephalitis virus and human immunodeficiency virus. Neurovirulence safety tests (NVST) are needed to identify neurovirulent vaccines that may cause CNS disease following vaccination. Progress: NSVT Development: Primate: Developed and tested a simplified, biologically relevant, standardized primate NVST. Animals inoculated with various doses of wild type and vaccine strains of mumps virus developed inflammation. Licensed mumps vaccines were statistically no different from experimental mumps vaccine. The test was unable to differentiate vaccine from wild type strains at a single dose. These studies support the conclusion that neurovirulence safety testing of mumps vaccines in primates may not be helpful in discriminating the neurovirulence potention in human CNS of mumps vaccine strains. Small animal: A newborn rat NVST was developed and tested with neurovirulent (Kilham, Strain 88-1961, Urabe AM9) and relatively non-neurovirulent (Jeryl-Lynn) strains of mumps viruses. Using physiological, neuroanatomical and behavioral endpoints, significant differences were identified in rats infected at birth with relatively neurovirulent and non neurovirulent viruses. This preliminary model system development was able to discriminate among vaccine strains and wild type strains based upon their known human neurovirulence clinical outcomes. Additional experiments are underway to complete validation of this model system and to evaluate a dose-response curve for neurovirulence induction by wild type and vaccine mumps virus strains.